Sepsis, a condition of enormous public health importance, has two-fold regional variation in mortality in the US, with the highest cluster in the Southeastern US. Few studies have had the large-scale, national, population-based design required to explain these regional variations. Our proposed study will capitalize on the infrastructure of the 30,000 subject REGARDS community-based cohort, which has the elements needed to identify individual and community-level sepsis risk factors and their mediating effects on regional sepsis variations. Our study will advance sepsis science by identifying individual and community-level factors amenable to risk reduction, potentially leading to strategies to prevent sepsis and reduce its high mortality. Our study objectives are 1) identify individual, family, community and societal/system healthcare factors associated with sepsis attack rates and case fatality, and 2) determine their mediating effects on regional sepsis variations. Sepsis is a dangerous syndrome of body-wide systemic inflammation triggered by microbial infection. Sepsis may injure vital organs, resulting in shock and death. Sepsis is a major community threat, resulting in over 750,000 hospitalizations and 215,000 deaths in the US annually - exceeding deaths resulting from acute myocardial infarction, lung cancer or breast cancer. Our recent study indicates a Southeastern US "belt" of two-fold excess sepsis mortality, reflecting almost 8,500 excess sepsis deaths annually. To understand the reasons for regional variations in sepsis mortality, a study must be able to identify the pre-hospital individual and community-level risk factors associated with sepsis attack rates and case fatality. However, few studies have had the large-scale, national, population-based design required to examine these relationships. We propose an ancillary study to the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study, an ongoing NINDS-funded national cohort of >30,000 community-dwelling adults. Using the well- established infrastructure of this large cohort study, we will identify sepsis hospitalizations and deaths, drawing upon over 3,300 events across a 10-year span. We will test associations between baseline individual and community healthcare-related characteristics (resources, access and quality of care) and the risks of incident sepsis and 28-day sepsis death (case fatality), determining their mediating influences on regional sepsis variations. The specific aims of this study are to 1) Determine US geographic variations in sepsis susceptibility (attack rate) and case fatality, 2) Determine the individual and family characteristics that mediate sepsis geographic variations and 3) Determine the community and societal/system healthcare characteristics that mediate sepsis geographic variations. PUBLIC HEALTH RELEVANCE: Sepsis is a life-threatening condition consisting of body-wide inflammation triggered by infections such as pneumonia, kidney infection, cellulitis or meningitis. This study will determine if certain individuals or communities are prone to develop sepsis. Information from this study will support strategies to reduce or prevent sepsis in the community. .